Lumacaftor is one of the active ingredients in ORKAMBI® tablets, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3 -benzodioxo-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid. The molecular formula for lumacaftor is C24H18F2N2O5. The molecular weight for Lumacaftor is 452.41. The structural formula is:

Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL).
ORKAMBI® is available as a pink, oval-shaped, film-coated tablet for oral administration containing 200 mg of Lumacaftor and 125 mg of Ivacaftor. Each ORKAMBI® tablet contains 200 mg of Lumacaftor and 125 mg of Ivacaftor, and the following inactive ingredients: microcrystalline cellulose; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. In-vitro studies have demonstrated that Lumacaftor acts directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.
Following multiple oral dose administrations of Lumacaftor, the exposure of Lumacaftor increased roughly proportionally with dose from 50 to 1000 mg qd. In subjects with cystic fibrosis (CF), the Lumacaftor Cmax and AUC also increases approximately proportional with the dose over the Lumacaftor 25 mg qd to 400 mg q12h dose range. The exposure of Lumacaftor increased approximately 1.6-to 2.0-fold when given with fat containing food. The median (range) time of the maximum concentration (tmax) is approximately 4.0 (2.0, 9.0) hours in the fed state.
When a single dose of Lumacaftor and Ivacaftor was administered with fat-containing foods, Lumacaftor exposure was approximately 2 times higher and Ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.
Following multiple oral dose administration of Lumacaftor in combination with Ivacaftor, the exposure of Lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) tmax of Lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.
Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L.
The half-life of Lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of Lumacaftor was estimated to be 2 38 L/hr (29.4%) for patients with CF.
Lumacaftor is not extensively metabolized in humans with the majority (51%) of Lumacaftor excreted unchanged in the feces. There was minimal elimination of Lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). In-vitro and in vivo data indicate that Lumacaftor is mainly metabolized via oxidation and glucuronidation.
Lumacaftor has low aqueous solubility and high permeability assessed via the colorectal adenocarcinoma (Caco-2) cell system. Although pH-dependent solubility was observed, the Lumacaftor drug substance is practically insoluble in water and buffer solutions of pH 1.0 to pH 8.0. Therefore, Lumacaftor is suggested to be a BCS Class 2 (low solubility/high permeability) compound.
Since Lumacaftor is considered a BCS class II, the drug substance was jet-milled early in development to reduce the particle size and potentially improve bioavailability. Based on these studies a control on Lumacaftor particle size in the drug substance specification was established.
Various formulations have been used in the development of Lumacaftor alone and in combination which includes suspension, capsules and tablets. Comparative exposure of the different formulations of Lumacaftor was seen in single dose studies in healthy volunteers. Exposure of the suspension is lower than that seen for capsules and tablets. Early clinical studies were conducted with the co-administration of both Ivacaftor and Lumacaftor. A cross-over study (007) was conducted to evaluate the relative bioavailability of the fixed dose combination tablet as compared to the separate tablets. The tablet and FDC appear to be bioequivalent, and the only parameter that did not meet standard bioequivalence criteria is the Cmax of Ivacaftor (GLSMR [90% CI]-1.20 [1.09, 1.33]). However, for practical purposes, this is acceptable and the PK results from tablet formulation can be considered applicable to the FDC as well.
The main medical concerns surrounding Lumacaftor is the 2-fold positive food effect when the drug is taken with a high fat meal. Elimination of the food effect would allow the administration of the drug on an empty stomach and more reliable plasma concentrations.
In order to overcome the problems associated with prior conventional Lumacaftor formulations and available drug delivery systems, novel complex formulations of Lumacaftor and salts or derivatives thereof together with complexation agents and pharmaceutically acceptable excipients were prepared. Novel complex formulations of the present invention are characterized by instantaneous redispersibility, increased apparent solubility, instantaneous dissolution, increased apparent permeability in fasted and fed state simulation that is expected to deliver full absorption and the elimination of the food effect.